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Additional results from a study comparing three HIV drug regimens indicates that Kaletra® (lopinavir/ritonavir) combined with two nucleoside reverse transcriptase inhibitors (NRTIs) is less likely to cause limb fat loss (peripheral lipoatrophy) than Sustiva® (efavirenz) plus two NRTIs. The new data follow on the heels of preliminary efficacy results from the same study suggesting that Sustiva has a few virologic advantages over Kaletra.

The study (A5142), conducted by the AIDS Clinical Trials Group, compared three drug regimens taken for almost two years: Kaletra plus two NRTIs, Sustiva plus NRTIs, and Kaletra plus Sustiva (without any NRTIs).

As for the NRTIs combined with Sustiva or Kaletra, the vast majority of patients used either Epivir® (lamivudine) or Emtriva® (emtricitabine). Approximately 42% also used Retrovir®, 24% used Zerit® (stavudine), and 34% used Viread® (tenofovir).

A5142, with an enrollment of 753 treatment-naive patients, is the first large study to compare Kaletra to Sustiva – two reigning standard-of-care options in the United States for HIV-positive people starting treatment for the first time.

The preliminary safety and efficacy analysis was reported at the XVI International AIDS Conference, held in Toronto in July. The metabolic outcomes analysis – involving changes in body fat composition and lipid (fat) levels in the blood – was reported today at the 14th Conference on Retroviruses and Opportunistic Infections (CROI).

According to the preliminary efficacy data reported in Toronto, the three treatment groups were concluded to be effective. However, there was one key difference between the treatment groups: the time to virologic failure – defined as a viral load that increased above 200 after being below this point during the study – was shorter in the Kaletra/NRTI group than in the Sustiva/NRTI group. Additionally, the percentage of patients who experienced virologic failure by week 96 of the study was 33% in the Kaletra/NRTI group, compared to 24% in the Sustiva/NRTI group.

As for the body fat parameters presented at CROI, a notable difference favored the use of Kaletra over Sustiva. After 96 weeks of treatment, 32% of patients in the Sustiva/NRTIs group had evidence of peripheral lipoatrophy – limb fat loss documented using dual-energy x-ray absorptiometry (DEXA) scanning – compared to 18% of patients in the Kaletra/NRTI group. In the Kaletra/Sustiva group, peripheral lipoatrophy was documented in 8% of patients.

While this difference between the Sustiva group and the Kaletra group is significant, it is important to note that the choice of NRTIs clearly played a role in the risk of limb fat loss. It was predominantly seen in patients taking either Zerit or Retrovir – two drugs that have been fingered as lipaotrophy culprits in other studies. Among patients in the Kaletra and Sustiva groups who used Viread instead, rates of peripheral lipoatrophy were not statistically greater than the risk in patients who took Sustiva/Kaletra without NRTIs.

It is important to note that measurements of facial fat loss – the most concerning symptom of lipoatrophy – were not conducted by the researchers.

Moderate increases in upper body (trunk) fat were seen in all three groups, with no statistically significant differences between the groups.

As for metabolic parameters, total cholesterol levels increased by 33 mg/dL in the Sustiva/NRTI group, 33 mg/dL in the Kaletra/NRTI group, and 57 mg/dL in the Sustiva/Kaletra group. The difference between the Sustiva/Kaletra group, compared to the total cholesterol levels in the Sustiva/NRTI and the Kaletra/NRTI groups, was stastically significant.

“Good” HDL cholesterol levels increased by 9, 8, and 16 mg/dL, and “bad” non-HDL cholesterol increased by 21, 26, and 43 mg/dL, respectively. The increases in the Sustiva/Kaletra group, compared to those in the Kaletra/NRTI and Sustiva/NRTI groups, were statistically significant.

With respect to triglyceride levels, increases of 14 mg/dL were seen in the Sustiva/NRTI group, 47 mg/dL in the Kaletra/NRTI group, and 63 mg/dL in the Sustiva/Kaletra group. The differences between the three groups were statistically significant.

In conclusion, results from A5142 continue to uncover some potentially important differences between Sustiva- and Kaletra-based treatment regimens. While there may be evidence of an efficacy advantage among those taking Sustiva plus two NRTIs as first-line therapy, the increased risk of peripheral lipoatrophy among those taking Sustiva plus two NRTIs is yet another noteworthy finding of this important study comparing two popular first-line treatment options.

Lopinavir/ritonavir (Kaletra) was less likely to cause fat loss (lipoatrophy) than efavirenz when paired with nucleoside analogues, analysis of the ACTG 5142 study has shown. The findings, presented on Monday at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles, show that while efavirenz suppressed viral load for longer, those who took the drug were almost twice as likely to experience fat loss in the face or limbs compared to those who took Kaletra.

A second study, of lopinavir/ritonavir maintenance monotherapy, also found that when compared to patients treated with efavirenz, AZT and 3TC, those who received Kaletra monotherapy were much less likely to lose limb fat after two years of treatment.

The two studies, both designed some years ago, reflect attempts to develop strategies that will spare patients drug toxicities associated with the nucleoside analogue drug class, which still forms the backbone of HIV treatment. Fat loss caused by the thymidine nucleoside analogues (d4T and AZT) is the most significant of these toxicities.

ACTG 5142 ACTG 5142 was a large randomised study that compared a nucleoside-sparing regimen of Kaletra and efavirenz against Kaletra or efavirenz paired with lamivudine (3TC) plus either d4T, AZT or tenofovir. The study was designed to test whether avoidance of nucleoside analogue drugs, some of which can cause lipoatrophy, was effective and safe.

Virological results of the study, presented at the International AIDS Conference in Toronto in August 2006 showed that patients randomised to Kaletra plus two NRTIs experienced virological rebound significantly more quickly than patients randomised to efavirenz plus two NRTIs. By intent-to-treat analysis, 89% of the participants receiving efavirenz-based triple therapy had viral loads below 50 copies/ml after 96 weeks, compared with 77% receiving Kaletra-based triple therapy (p=0.003). Kaplan-Meier analysis showed that recipients of Kaletra-based triple therapy had a significantly faster time to virological failure than the efavirenz triple therapy arm (P=0.006)

The study recruited 753 patients in the United States, 64% non-Caucasian and 20% female. The median baseline CD4 cell count was 191 cells/mm3 and the median baseline limb fat as measured by DEXA scan was 7.1kg.

In the two-nucleoside analogue-containing arms, 42% received AZT, 24% d4T and 34% tenofovir as their second nucleoside analogue.

After 96 weeks those in the nucleoside-sparing arm had experienced an average 18% gain in limb fat (around 1kg), compared to a 9.8% gain in the Kaletra + 2 NRTIs group and a gain of 1.4% in the efavirenz group.

Lipoatrophy, defined as a 20% loss of limb fat at week 96, was experienced by 32% of the efavirenz + 2NRTI group, 17% of the Kaletra + 2 NRTI group, and 9% of the Kaletra/efavirenz group.

When the incidence of lipoatrophy was analysed according to the second nucleoside analogue used, it was most commonly seen in patients who received d4T – 42% compared to 27% in the AZT group. This difference was statistically significant. Nine per cent of tenofovir-treated patients developed lipoatrophy, a significantly lower proportion than the AZT recipients.

When lipoatrophy incidence was analysed according to pairings of drugs, it was evident that tenofovir recipients who received efavirenz were more likely to develop lipoatrophy (12%) than those who received Kaletra (6%). Similarly, AZT recipients who received efavirenz were also at greater risk of lipoatrophy (40% vs 16% for Kaletra recipients). The difference was less pronounced for d4T recipients (51% for efavirenz, 33% for Kaletra).

Total cholesterol and triglyceride increases were significantly higher in the nucleoside-sparing arm than in the Kaletra arm (+57mg/dL vs 32mg/dL, p=0.001; +62mg/dL vs 46mg/dL, p=0.03)); there was no significant difference in cholesterol elevation between the Kaletra and efavirenz arms. The increase in HDL cholesterol was significantly greater in the nucleoside-sparing arm.

Presenting the results, Richard Haubrich of the University of California, San Diego, said that revision of treatment guidelines would need to take into account the effects of different regimens on body fat distribution.

A second study showed that, unsurprisingly, removing the thymidine analogue from a treatment regimen and providing Kaletra monotherapy after an induction phase of triple therapy resulted in a substantially lower risk of lipoatrophy over two years of follow-up. But perhaps the most striking aspect of this study was the high level of lipoatrophy in the efavirenz/AZT/3TC control arm: 34% of patients had lost at least 20% of their limb fat by week 96, DEXA scans showed.

The Abbott-sponsored study, reported by Bill Cameron of the University of Ottawa, randomised 155 antiretroviral-naïve patients to AZT/3TC plus either Kaletra or efavirenz. After 24 weeks patients in the Kaletra arm with undetectable viral load were randomised to drop their nucleoside analogues and continue with Kaletra maintenance therapy, or to continue with triple therapy.

DEXA scan data after 96 weeks of follow-up were available for 74 in the Kaletra arm and 32 in the efavirenz arm. Thirty-four per cent of the efavirenz group had lost 20% of their limb fat at week 96, the endpoint used to define lipoatrophy in this study, compared to 5% of all Kaletra-treated patients. There was no significant difference in the proportions that experienced an increase in trunk fat of at least 20% (45% vs 44%), but only efavirenz-treated patients experienced both fat loss and fat gain in the different body fat compartments.

The researchers found that truncal fat gain was associated only with a lower baseline CD4 count, not treatment, and that even though a lower baseline CD4 count was associated with a greater increase in limb fat too, efavirenz-treated patients had smaller increases in limb fat when limb fat gain was analysed according to baseline CD4 count.

These findings, although complicated by the presence of AZT/3TC in one arm in addition to efavirenz, are likely to raise further concerns about the long-term toxicity of efavirenz-containing regimens at a time when there is a growing emphasis on the need for long-term treatment to carry the lowest possible risk of serious toxicity.

They will also provoke further interest in the long-term potential of Kaletra-based induction/maintenance regimens.

Commenting on the findings, Bill Cameron remarked that the study showed that the combination of nucleoside analogues and a protease inhibitor appears to pose less of a risk of lipoatrophy than previously thought. Previous assumptions, he said, had been based on a study of nelfinavir plus d4T/3TC or AZT/3TC, and just as all nucleoside analogues are not created equal where mitochondrial toxicity is concerned, “so too there appear to be differences within the protease inhibitor class with regard to fat sparing.”